Project Summary/Abstract Alzheimer's disease (AD) is a devastating complex neurological degenerative disorder affecting 10% of people over 65 with no cure. The overarching goal of the proposed study is to identify and functionally characterize AD-associated SNPs utilizing novel functional genomic approaches and iPSC-derived cellular models. Our plans include: (1) Determine the functional significance of candidate SNPs in three iPSC-drived 2D AD relevant cell types. (2) Identify genes regulated by distal non-coding SNPs in three iPSC-drived 2D AD relevant cell types. (3) Test the biological consequences of high confidence AD rSNPs from (1) and (2) in isogenic iPSC- derived 2D cell cultures and 3D minibrain organoids. The designed study will be very first comprehensive investigation of AD associated SNPs, thus will shed light on how non-coding genetic variations contribute to AD. Obtaining knowledge for the fundamental genetic mechanisms of AD will expand our horizons to develop improved preventative and diagnostic methods, and also yield targets for novel therapeutic interventions, ultimately leading to a cure for AD.